Directing cell migration and organization via nanocrater-patterned cell-repellent interfaces.

Although adhesive interactions between cells and nanostructured interfaces have been studied extensively, there is a paucity of data on how nanostructured interfaces repel cells by directing cell migration and cell-colony organization. Here, by using multiphoton ablation lithography to pattern surfaces with nanoscale craters of various aspect ratios and pitches, we show that the surfaces altered the cells focal-adhesion size and distribution, thus affecting cell morphology, migration and ultimately localization. We also show that nanocrater pitch can disrupt the formation of mature focal adhesions to favour the migration of cells towards higher-pitched regions, which present increased planar area for the formation of stable focal adhesions. Moreover, by designing surfaces with variable pitch but constant nanocrater dimensions, we were able to create circular and striped cellular patterns. Our surface-patterning approach, which does not involve chemical treatments and can be applied to various materials, represents a simple method to control cell behaviour on surfaces

Voices

Microfabricated and microfluidic devices enable standardized handling, precise spatiotemporal manipulation of cells and liquids, and recapitulation of cellular environments, tissues, and organ-level biology. We asked researchers how these devices can make in vitro experiments more physiologically relevant.Dissecting Biological Complexity / Lydia L. Sohn Improve Reproducibility! / Petra Schwille Enabling Physiological Conditions / Andreas Hierlemann Controlling Space and Time Organs-on-Chips Multicellular Microfluidics Beyond Just Shear Force

Impact of organ-on-a-chip technology on pharmaceutical R&D costs

Healthcare systems are faced with the challenge of providing innovative treatments, while shouldering high drug costs that pharmaceutical companies justify by the high costs of R&amp;D. An emergent technology that could transform R&amp;D efficiency is organ-on-a-chip. The technology bridges the gap between preclinical testing and human trials through better predictive models, significantly impacting R&amp;D costs. Here, we present an expert survey on the future role of organ-on-a-chip in drug discovery and its potential quantitative impact. We find that the technology has the potential to reduce R&amp;D costs significantly, driven by changes in direct costs, success rates and the length of the R&amp;D process. Finally, we discuss regulatory challenges to efficiency improvements.</p

Recommendations on fit-for-purpose criteria to establish quality management for microphysiological systems and for monitoring their reproducibility.

Cell culture technology has evolved, moving from single-cell and monolayer methods to 3D models like reaggregates, spheroids, and organoids, improved with bioengineering like microfabrication and bioprinting. These advancements, termed microphysiological systems (MPSs), closely replicate tissue environments and human physiology, enhancing research and biomedical uses. However, MPS complexity introduces standardization challenges, impacting reproducibility and trust. We offer guidelines for quality management and control criteria specific to MPSs, facilitating reliable outcomes without stifling innovation. Our fit-for-purpose recommendations provide actionable advice for achieving consistent MPS performance

Breast cancer-on-chip for patient-specific efficacy and safety testing of CAR-T cells

Physiologically relevant human models that recapitulate the challenges of solid tumors and the tumor microenvironment (TME) are highly desired in the chimeric antigen receptor (CAR)-T cell field. We developed a breast cancer-on-chip model with an integrated endothelial barrier that enables the transmigration of perfused immune cells, their infiltration into the tumor, and concomitant monitoring of cytokine release during perfused culture over a period of up to 8 days. Here, we exemplified its use for investigating CAR-T cell efficacy and the ability to control the immune reaction with a pharmacological on/off switch. Additionally, we integrated primary breast cancer organoids to study patient-specific CAR-T cell efficacy. The modular architecture of our tumor-on-chip paves the way for studying the role of other cell types in the TME and thus provides the potential for broad application in bench-to-bedside translation as well as acceleration of the preclinical development of CAR-T cell products.Stem cells & developmental biolog

Biology-inspired microphysiological systems to advance patient benefit and animal welfare in drug development

The first microfluidic microphysiological systems (MPS) entered the academic scene more than 15 years ago and were considered an enabling technology to human (patho)biology in vitro and, therefore, provide alternative approaches to laboratory animals in pharmaceutical drug development and academic research. Nowadays, the field generates more than a thousand scientific publications per year. Despite the MPS hype in academia and by platform providers, which says this technology is about to reshape the entire in vitro culture landscape in basic and applied research, MPS approaches have neither been widely adopted by the pharmaceutical industry yet nor reached regulated drug authorization processes at all. Here, 46 leading experts from all stakeholders - academia, MPS supplier industry, pharmaceutical and consumer products industries, and leading regulatory agencies - worldwide have analyzed existing challenges and hurdles along the MPS-based assay life cycle in a second workshop of this kind in June 2019. They identified that the level of qualification of MPS-based assays for a given context of use and a communication gap between stakeholders are the major challenges for industrial adoption by end-users. Finally, a regulatory acceptance dilemma exists against that background. This t4 report elaborates on these findings in detail and summarizes solutions how to overcome the roadblocks. It provides recommendations and a roadmap towards regulatory accepted MPS-based models and assays for patients' benefit and further laboratory animal reduction in drug development. Finally, experts highlighted the potential of MPS-based human disease models to feedback into laboratory animal replacement in basic life science research.Toxicolog

Vom Photolack zum Gecko

Beobachtet man Geckos, die über Wände und Decken jagen, fragt man sich, welche Kräfte sie halten. Verantwortlich für dieses Kunststück sind elektromagnetische Kräfte zwischen Molekülen, insbesondere van der Waals-Kräfte zwischen fluktuierenden Dipolen. Diese entscheiden auch darüber, ob eine Beschichtung auf einem Substrat hält, sei es ein Photolack auf einem Siliziumwafer oder ein bakterienhaltiger Biofilm auf einer Türklinke oder einem Zahn

Organs-on-a-chip – Microphysiological platforms as in vitro models of cardiac and adipose tissue

Toxicological screening and drug discovery to date has relied on animal models and conventional cell culture, which are useful, but fail to resemble human physiology. The discovery of human induced pluripotent stem (iPS) cells has led to the emergence of a new paradigm of screening using human disease-specific organ-like cultures in a dish. One promising approach to produce these organ-like structures is the use of microfluidic devices, which can simulate 3D tissue structure and function with microphysiological features. Using microfabrication techniques we have developed two microphysiological platforms (MPSs) that incorporate 3D in vitro models of human cardiac and adipose tissue. Both MPSs consist of three functional components: (i) a tissue culture chamber mimicking geometrical organ-specific in vivo properties; (ii) “vasculature-like” media channels enabling a precise and computationally predictable delivery of compounds (nutrients, drugs); and (iii) “endothelial like” barriers protecting the tissues from shear forces while allowing diffusive transport. Both organ-chips are able to create physiological micro-tissues that are viable and functional for multiple weeks. The developed cardiac MPS is the first system that combines human genetic background, physiologically relevant tissue structure and “vasculature-like” perfusion. Pharmacological studies using it show half maximal inhibitory/effective concentration values (IC50/EC50) that are more consistent with data from primary tissue references compared to cellular scale studies. The cardiac and adipose MPSs are both extremely versatile and can be applied for toxicological screening as well as fundamental research

Microphysiological stem cell models of the human heart

Models of heart disease and drug responses are increasingly based on human pluripotent stem cells (hPSCs) since their ability to capture human heart (dys-)function is often better than animal models. Simple monolayer cultures of hPSC-derived cardiomyocytes, however, have shortcomings. Some of these can be overcome using more complex, multi cell-type models in 3D. Here we review modalities that address this, describe efforts to tailor readouts and sensors for monitoring tissue- and cell physiology (exogenously and in situ) and discuss perspectives for implementation in industry and academia.Stem cells & developmental biolog